Hydrophobic effect protein folding

Fig. 5. Protein folding. The unfolded polypeptide chain coUapses and assembles to form simple stmctural motifs such as -sheets and a-hehces by nucleation-condensation mechanisms involving the formation of hydrogen bonds and van der Waal s interactions. Small proteins (eg, chymotrypsin inhibitor 2) attain their final (tertiary) stmcture in this way. Larger proteins and multiple protein assembhes aggregate by recognition and docking of multiple domains (eg, -barrels, a-helix bundles), often displaying positive cooperativity. Many noncovalent interactions, including hydrogen bonding, van der Waal s and electrostatic interactions, and the hydrophobic effect are exploited to create the final, compact protein assembly. Further stmctural...

Hydrophobic interactions are the single most important stabilizing influence of protein native structure. The hydrophobic effect refers to the tendency of non-polar substances to minimize contact with a polar solvent such as water. Non-polar amino acid residues constitute a significant proportion of the primary sequence of virtually all polypeptides. These polypeptides will fold in such a way as to maximize the number of such non-polar residue side chains buried in the polypeptide s interior, i.e. away from the surrounding aqueous environment. This situation is most energetically favourable. 

The van der Waals model of monomeric insulin (1) once again shows the wedge-shaped tertiary structure formed by the two chains together. In the second model (3, bottom), the side chains of polar amino acids are shown in blue, while apolar residues are yellow or pink. This model emphasizes the importance of the hydrophobic effect for protein folding (see p. 74). In insulin as well, most hydrophobic side chains are located on the inside of the molecule, while the hydrophilic residues are located on the surface. Apparently in contradiction to this rule, several apolar side chains (pink) are found on the surface. However, all of these residues are involved in hydrophobic interactions that stabilize the dimeric and hexameric forms of insulin. 

Most proteins fold spontaneously into their native conformation, even in the test tube. In the cell, where there are very high concentrations of proteins (around 350 g L ), this is more dif cult. In the unfolded state, the apolar regions of the peptide chain (yellow) tend to aggregate—due to the hydrophobic effect (see p. 28)—with other proteins or with each other to form insoluble products (2). In addition, unfolded proteins are suscep-... 

Lins L, Brasseur R. The hydrophobic effect in protein folding. FASEB J 1995 9 535-540. 

The folding of proteins into their characteristic three-dimensional shape is governed primarily by noncovalent interactions. Hydrogen bonding governs the formation of a helices and [) sheets and bends, while hydrophobic effects tend to drive the association of nonpolar side chains. Hydrophobicity also helps to stabilize the overall compact native structure of a protein over its extended conformation in the denatured state, because of the release of water from the chain s hydration sheath as the protein... 

It should be noted that liposomes in effect mimic cell walls and proteins are to be found in nature associated with cell walls. However, the association may differ physical according to the conformation for the protein under consideration. For example some proteins fold so that they are exposing hydrophobic regions which lit into the hydrophobic regions of the liposomal structure (or cell wall). The net effect is that the transbilayer protein exposes its hydrophilic regions both inside and outside of the liposomal structure to the water surrounding the structure (Figure 9.6). 

The simplest interpretation is that AH for protein folding has a large ACp term, as described in Chapter 17 for overall denaturation. If the transition state for folding is relatively compact and shields the hydrophobic side chains, then there will be the characteristic ACp term associated with the hydrophobic effect (cf. equation 17.1) ... 

Ensembles 600 Enterokinase 480 Enthalpy 55 activation 56, 545-547 protein folding 509 -512 specific heat effects 511, 545 - 547 Enthalpy-entropy compensation 346 Enthalpy versus entropy in protein folding 509-512, 587, 599 Entropy 55, 68-72 activation 56, 545 -547 binding 324, 345 Boltzmann equation 510 chelate effect 345 configurational 510 configurational entropy of loops 535 effective concentration 68-72 equilibria on enzyme surface 118 hydrogen bond 338 hydrophobic bond 332, 510 importance in enzyme catalysis 72 importance in enzyme-substrate binding 72... 

Hydrophobic Effects. Hydrogen bonds and van der Waals forces are of major importance in determining the secondary structures formed by fibrous proteins. To understand the complex folded structures found in globular proteins additional types of interactions between amino acid side chains... 

The same type of entropic effect plays a major role in directing the folding of globular proteins. About half of the amino acid side chains in proteins are hydrophobic (e.g., alanine, valine, isoleucine, leucine, and phenylalanine). Entropic effects strongly favor internal locations for these side chains where they are free from contacts with water (e.g., see fig. 1.12, which shows the location of polar and apolar side chains in cytochrome c). 

Litowski, J. R., and Hodges, R. S. (2002). Designing heterodimeric two-stranded alpha-helical coiled-coils - Effects of hydrophobicity and alpha-helical propensity on protein folding, stability, and specificity. J. Biol. Chem. 277, 37272-37279. 

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